ABSTRACT In food and drug allergy, anaphylaxis, allergic rhinitis, asthma and other forms of acute and chronic allergic diseases, eosinophils and mast cells, through release of preformed and newly generated mediators, granule proteins, cytokines and other mediators are felt to be key effector cells. Eosinophils and mast cells are also implicated in other type 2 immunologic diseases including chronic rhinosinusitis, eosinophilic esophagitis and atopic dermatitis. For many allergic diseases, drugs that inhibit mast cell degranulation, reduce eosinophil numbers, or counteract their released mediators are useful therapies, but all remain incompletely effective. Siglec-6 and Siglec-8 are members of the CD33-related subfamily of sialic acid-binding immunoglobulin-like lectins (siglecs). Siglec-6 is found on human mast cells, some B cells and cyto- and syncytiotrophoblasts of the placenta, while Siglec-8 is expressed on human eosinophils, mast cells and weakly on basophils. These transmembrane proteins contain N-terminal extracellular lectin binding domains that recognize distinct glycan ligands, and c-terminal intracellular domains including putative ITIM and ITSM signaling motifs. Both Siglec-6 (no mouse counterpart) and Siglec-8 (with Siglec-F being its closest mouse counterpart) preferentially and uniquely recognize specific glycan ligand structures. Engagement of Siglec-8/-F with antibodies or artificial ligands causes eosinophil death. Mice deficient in Siglec-F, or deficient in the airway mucin Muc5b, which carries sialoside ligands for Siglec-F, display exaggerated allergic eosinophilic pulmonary inflammation. Siglec-8 on mast cells, in contrast, does not influence cell survival, but instead functions to inhibit IgE-mediated activation. Less is known about Siglec-6, a prominently expressed human mast cell protein. Available data suggest that Siglec-6 may also function as an inhibitory receptor, and both Siglec-6 and Siglec-8 appear to possess inhibitory activity for both IgE- and non-IgE-mediated mast cell responses. The overall goal of Project 1 is to exploit specific eosinophil and mast cell Siglecs to prevent or treat immediate allergic reactions and chronic allergic inflammation. In particular, Siglec-6 and Siglec-8 provide selective targets for manipulating mast cell and/or eosinophil responses. These concepts will be explored in three specific aims using novel Siglec-6 and Siglec-8 knock-in mice and humanized mice in studies highly integrated with other projects by delineating Siglec-6 and Siglec-8 function and signaling properties in eosinophils and mast cells (Aim 1, with Project 2 and Core B), defining and exploiting Siglec-8 and its ligands for their anti-eosinophil properties in models of chronic eosinophilic inflammation (Aim 2, with Project 2), and exploiting specific ligands of Siglec-6 and Siglec-8 for their anti-mast cell and eosinophil effects (Aim 3, , with Project 2, Project 3 and Core B).